Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy

Abstract

The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide, and the resulting cardiac complications are the leading cause of death. Among these complications is diabetes-induced cardiomyopathy (DCM), which is the consequence of a pro-inflammatory condition, oxidative stress and fibrosis caused by hyperglycemia. Cardiac remodeling will lead to an imbalance in cell survival and death, which can promote cardiac dysfunction. Since the conventional treatment of DM generally does not address the prevention of cardiac remodeling, it is important to develop new alternatives for the treatment of cardiovascular complications induced by DM. Thus, therapy with mesenchymal stem cells has been shown to be a promising approach for the prevention of DCM because of their anti-apoptotic, anti-fibrotic and anti-inflammatory effects, which could improve cardiac function in patients with DM.

Keywords: cardiac remodeling; diabetes mellitus; diabetic cardiomyopathy; fibrosis; mesenchymal stromal cells; oxidative stress; pro-inflammatory cytokines.

Figure 1

Cardiac functional and morphological alterations in diabetic cardiomyopathy (DCM). Different processes underlie the establishment of DCM, although oxidative stress and tissue inflammation seem to be responsible for maintaining the changes observed in diabetic hearts. Preclinical studies in rodents evidenced alterations in signaling pathways and protein expression related to cardiac dysfunction, which may be relevant targets for the development of new strategies for the treatment of DCM. AGE, advanced glycation end products; ANP, atrial natriuretic peptide; ERK, extracellular signal-regulated kinase; FNDC5, full-length type III fibronectin containing 5; GSH-Px, glutathione peroxidase; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; iNOS, inducible nitric oxide synthase; MHC, myosin heavy chain; NOX2, reduced nicotinamide adenine dinucleotide phosphate-oxidase 2; PKC, protein kinase C; RAGE, receptor for advanced glycation end products; SIRT1, sirtuin 1; SMA, smooth muscle actin; SOD, superoxide dismutase; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1. ↑ increased; ↓ reduced.

Figure 2

Beneficial effects of mesenchymal stromal cells (MSCs) observed in preclinical models of diabetes. Extracellular vesicle secretion by MSCs derived from adult (bone marrow, adipose tissue) or embryonic tissue-derived (placenta) restores endothelial and cardiomyocyte functions, reverting cardiac hypertrophy and the reduced contractility observed in diabetic animals. In addition to this, by lowering the activation of inflammatory cells and fibroblasts, MSCs reduce myocyte apoptosis and the fibrotic remodeling seen in rodent models.